Structure and Dynamics of the Integrin LFA-1 I-Domain in the Inactive State Underlie its Inside-Out/Outside-In Signaling and Allosteric Mechanisms
Leung, Hoi Tik Alvin
De, Simone Alfonso
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Kukic, P., Leung, H. T. A., Bemporad, F., Aprile, F., Kumita, J., De, S. A., Camilloni, C., & et al. (2015). Structure and Dynamics of the Integrin LFA-1 I-Domain in the Inactive State Underlie its Inside-Out/Outside-In Signaling and Allosteric Mechanisms. Structure, 23 745-753. https://doi.org/10.1016/j.str.2014.12.020
Highlights • We identified three substates in the apo LFA-1 I-domain using RAM simulations • Independent RDC measurements were accurately reproduced using the three substates • The three substates correspond to the inactive, low, and intermediate affinity states • The three substates are associated with the precise regulation of the LFA-1 binding Summary Lymphocyte function-associated antigen 1 (LFA-1) is an integrin that transmits information in two directions across the plasma membrane of leukocytes, in so-called outside-in and inside-out signaling mechanisms. To investigate the structural basis of these mechanisms, we studied the conformational space of the apo I-domain using replica-averaged metadynamics simulations in combination with nuclear magnetic resonance chemical shifts. We thus obtained a free energy landscape that reveals the existence of three conformational substates of this domain. The three substates include conformations similar to existing crystallographic structures of the low-affinity I-domain, the inactive I-domain with an allosteric antagonist inhibitor bound underneath α helix 7, and an intermediate affinity state of the I-domain. The multiple substates were validated with residual dipolar coupling measurements. These results suggest that the presence of three substates in the apo I-domain enables the precise regulation of the binding process that is essential for the physiological function of LFA-1.
This study was supported by the Wellcome Trust and the BBSRC.
External DOI: https://doi.org/10.1016/j.str.2014.12.020
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247847
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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